This invention relates to a prophylactic and therapeutic agent for circulatory disorders, more particularly to a prophylactic and therapeutic agent for cerebral, cardiac or peripheral circulatory disorders accompanied with various ischemic diseases, especially to a prophylactic and therapeutic agent for circulatory disorders which is useful as an inhibitor against lipid peroxidation and/or an agent for normalizing cerebral dysfunctions.
In the specification, the term "circulatory disorders" means diseases due to circulatory disorder.
In cerebral, cardiac or peripheral circulatory disorders, as a result of ischemia (the state where little blood is supplied to tissues), active oxygens (OH.radical, superoxide, etc.) formed in the tissues therearound act on unsaturated fatty acids including arachidonic acid liberated from cell membranes, to form peroxidized lipids. Such changes will occur not only during ischemia, but also further will be accelarated and advanced by reoxidation through the blood refeeding after the ischemia to cause damage of cell membrane enriched in unsaturated fatty acids, destruction of surrounding tissues, destruction of blood vessel endothelium, blood vessel spasms or cerebral edema, etc., and the condition of disease will be advanced according to a vicious circle of a series of these reactions, as is well known in the art ("Cerebral Ischemia and Cell Disorder", edited by Takao Asano, Neuron Co., 1980; "Cerebral Ischemia and Free Radical", edited by Takao Asano, Neuron Co., 1983).
Accordingly, if lipid peroxidation by active oxygen could be inhibited, it would be possible to prevent destruction of cell membrane, destruction of blood vessel endothelium, blood vessel spasm, cerebral edema, etc., and give a prophylactic or therapeutic agent for circulatory disorders of a new type which can act on the cause of a disease, as different from the medicines of the prior art which ameliorates circulation by increasing the blood flow. Particularly, in recent years, effectiveness of such vasodilators is considerted to be doubtful and it is even said to be rather an adverse effect in cerebral insufficiency in the acute stage, and therefore such a pharmaceutical is further becoming more important.
As described above, peroxidized lipids is considered to be formed by the action of active oxygen as a result of ischemia. As the medicines which can inhibit lipid peroxidation by active oxygen, there have been known vitamin E, idebenone represented by the following formula: ##STR2## (Biochemical and Biophysical Research Communications 125, 1046 (1984); Report from Takeda Kenkyusho 44, 30 (1985)) and nizofenone represented by the following formula: ##STR3## (Journal of Neurochemistry, 37, 934 (1981)).
However, these medicines have drawbacks such that vitamin E has only unsatisfactory action, that idebenone and nizofenone are prepared by lengthy synthetic routes, that idebenone is considered to involve a problem in formation of a preparation for injection due to difficulty in solubilizing in water and also that nizofenone has potent central nervous system depressant activity [Study of Pharmaceuticals (Iyakuhin Kenkyu) 16, 1 (1985)].
Particularly, as the cerebral circulatory disorders, there may be mentioned various cerebral diseases such as cerebrovascular disorders, cerebral dysfunctions, vascular dementia, cerebrovascular tissue lesions accompanied with aging, etc. In these diseases, symptoms such as consciousness disorders, lowering in memory, etc., based on cerebral dysfunctions, namely the abnormal pattern of electroencephalogram will be caused. Therefore, as the medicine to be used for prophylaxis and therapy of these cerebral disorders, those having antagonistic action against drowsy pattern of electroencephalogram during cerebral function abnormality (abnormal electroencephalogram) (hereinafter referred to as "electroencephalogram normalizing action") have been desired.
As a medicine having such pharmacological activity, thyrotropine releasing hormone (TRH) having a chemical structure of L-pyrroglutamyl-L-histidyl-L-prolineamide has been known [Neuropharmacology, 14, 489 (1975); Journal of Pharmacology and Experimental Therapeutics 193, 11 (1975)]. However, TRH exhibites an action which is deemed to be a side action in clinic, also against electroencephalogram under normal state. Also, since TRH is a tripeptide, there is a fear that it has a problem in stability in living body or absorption by oral administration, and the dosage form at the present time is only by way of intravenous administration.
Various pyrazolone derivatives have been known in the art.
Japanese Unexamined Patent Publication No. 13766/1976 discloses a pyrazolin-5-one derivative represented by the following formula and its use as antithrombus agent: ##STR4## Japanese Unexamined Patent Publication No. 141517/1984 discloses use of the same compound as a therapeutic agent for cardiac infarction, inflammation, astham, etc., after myocardial ischemia.
Japanese Unexamined Patent Publication No. 175469/1984 discloses a pyrazolin-5-one derivative of the following formula and its use as a lipoxygenase inhibitor: ##STR5## (wherein X represents a group --CH.sub.2 CH.sub.2 O--, --CH.sub.2 CH.sub.2 S--, etc., and R represents an aryl group).
Japanese Patent Publication No. 512/1984 discloses a pyrazolin-5-one derivative and its use as a diuretic, antihypertensive, and antithrombosis: ##STR6## (wherein R.sub.1 represents a hydrogen atom or an amino group, R.sub.2 an aryl group and X represents a group --CH.sub.2 CH.sub.2 --, etc.).
However, these derivatives are not of the type in which all the aryl groups are bonded directly to the 1-position of the pyrazolin-5-one nucleus, and there is no description about the effect on cerebral dysfunctions including electroencephalogram normalizing action at all.
Also, West Germany Patent No. 28 36 891 discloses a pyrazolin-5-one derivative of the following formula and its use as antiinflammatory agent: ##STR7## (wherein R.sub.1 and R.sub.2 represent a hydrogen atom or a substituent).
However, there is no description about the action of inhibiting lipid peroxidation by active oxygen. Also, while the compound represented by the formula (B) is stated to be effective in models of ischemic heart diseases using rats, rabbits and dogs, it is ineffective in a model using pigs, of which circulation state is approximate to that of human heart. This result well coincides with the report that it is ineffective for ischemic heart diseases in human being (European Journal of Pharmacology, 114, 189 (1985)). Also, there is no description about a specific action concerning protection after recirculation of cerebral ischemia.